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Regulation of cardiac myocyte cell death and differentiation by myocardin

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Abstract

Myocardin is a cardiac- and smooth muscle-enriched transcriptional co-activator that was originally described as an interacting partner of the serum response factor. Shortly after myocardin’s discovery, a wealth of published literature described the role of myocardin as a regulator of smooth muscle differentiation and phenotype modulation, while gene-targeting studies confirmed the essential role of myocardin in vascular development. More recently, myocardin has been implicated as an important regulator of cardiac myocyte differentiation in studies demonstrating direct programming of fibroblasts towards the cardiac lineage. This function of myocardin has been attributed to its physical interaction with cardiac-enriched transcription factors such as MEF2C, GATA4, and TBX5. Moreover, conditional knockout models have revealed a critical role for myocardin during cardiac chamber maturation, and a surprising function for myocardin in the regulation of cardiomyocyte proliferation, cell death, and possibly mitochondrial function. This review summarizes the literature surrounding the cardiac-specific roles of myocardin during development and post-natal cardiac remodeling. In addition, we take a bioinformatics and computational approach to discuss known and predicted interactions and biological functions of myocardin, which suggests areas for future research.

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References

  1. Harvey RP (2002) Patterning the vertebrate heart. Nat Rev Genet 3:544–556

    Article  CAS  PubMed  Google Scholar 

  2. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Sci N Y NY 313:1922–1927

    Article  CAS  Google Scholar 

  3. Miano JM, Ramanan N, Georger MA et al (2004) Restricted inactivation of serum response factor to the cardiovascular system. Proc Natl Acad Sci USA 101:17132–17137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kwon C, Han Z, Olson EN, Srivastava D (2005) MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci USA 102:18986–18991. doi:10.1073/pnas.0509535102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang D, Chang PS, Wang Z et al (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105:851–862

    Article  CAS  PubMed  Google Scholar 

  6. Creemers EE, Sutherland LB, Oh J et al (2006) Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR. Mol Cell 23:83–96

    Article  CAS  PubMed  Google Scholar 

  7. Oh J, Wang Z, Wang D-Z et al (2004) Target gene-specific modulation of myocardin activity by GATA transcription factors. Mol Cell Biol 24:8519–8528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang C, Cao D, Wang Q, Wang D-Z (2011) Synergistic activation of cardiac genes by myocardin and Tbx5. PLoS ONE 6:e24242. doi:10.1371/journal.pone.0024242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Miano JM (2015) Myocardin in biology and disease. J Biomed Res 29:3–19. doi:10.7555/JBR.29.20140151

    PubMed  Google Scholar 

  10. Pipes GCT, Creemers EE, Olson EN (2006) The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev 20:1545–1556

    Article  CAS  PubMed  Google Scholar 

  11. Wang Z, Wang D-Z, Pipes GCT, Olson EN (2003) Myocardin is a master regulator of smooth muscle gene expression. Proc Natl Acad Sci USA 100:7129–7134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li S, Wang D-Z, Wang Z et al (2003) The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proc Natl Acad Sci USA 100:9366–9370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Du KL, Ip HS, Li J et al (2003) Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol Cell Biol 23:2425–2437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen J, Kitchen CM, Streb JW, Miano JM (2002) Myocardin: a component of a molecular switch for smooth muscle differentiation. J Mol Cell Cardiol 34:1345–1356

    Article  CAS  PubMed  Google Scholar 

  15. Yoshida T, Sinha S, Dandré F et al (2003) Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ Res 92:856–864

    Article  CAS  PubMed  Google Scholar 

  16. Parmacek MS (2008) Myocardin: dominant driver of the smooth muscle cell contractile phenotype. Arterioscler Thromb Vasc Biol 28:1416–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Long X, Bell RD, Gerthoffer WT et al (2008) Myocardin is sufficient for a smooth muscle-like contractile phenotype. Arterioscler Thromb Vasc Biol 28:1505–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang D-Z, Olson EN (2004) Control of smooth muscle development by the myocardin family of transcriptional coactivators. Curr Opin Genet Dev 14:558–566. doi:10.1016/j.gde.2004.08.003

    Article  CAS  PubMed  Google Scholar 

  19. Wang Z, Wang D-Z, Hockemeyer D et al (2004) Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428:185–189

    Article  CAS  PubMed  Google Scholar 

  20. Liu Z-P, Wang Z, Yanagisawa H, Olson EN (2005) Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell 9:261–270

    Article  PubMed  Google Scholar 

  21. Liu Y, Sinha S, McDonald OG et al (2005) Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem 280:9719–9727

    Article  CAS  PubMed  Google Scholar 

  22. Pidkovka NA, Cherepanova OA, Yoshida T et al (2007) Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circ Res 101:792–801

    Article  CAS  PubMed  Google Scholar 

  23. Deaton RA, Gan Q, Owens GK (2009) Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. Am J Physiol Heart Circ Physiol 296:H1027–H1037. doi:10.1152/ajpheart.01230.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tang R-H, Zheng X-L, Callis TE et al (2008) Myocardin inhibits cellular proliferation by inhibiting NF-kappaB(p65)-dependent cell cycle progression. Proc Natl Acad Sci USA 105:3362–3367. doi:10.1073/pnas.0705842105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen J, Yin H, Jiang Y et al (2011) Induction of microRNA-1 by myocardin in smooth muscle cells inhibits cell proliferation. Arterioscler Thromb Vasc Biol 31:368–375. doi:10.1161/ATVBAHA.110.218149

    Article  CAS  PubMed  Google Scholar 

  26. Jiang Y, Yin H, Zheng X-L (2010) MicroRNA-1 inhibits myocardin-induced contractility of human vascular smooth muscle cells. J Cell Physiol 225:506–511. doi:10.1002/jcp.22230

    Article  CAS  PubMed  Google Scholar 

  27. Gordon JW, Pagiatakis C, Salma J et al (2009) Protein kinase A-regulated assembly of a MEF2middle dotHDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells. J Biol Chem 284:19027–19042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ehyai S, Dionyssiou MG, Gordon JW et al (2015) A p38 mitogen-activated protein kinase-regulated myocyte enhancer factor 2-β-catenin interaction enhances canonical Wnt signaling. Mol Cell Biol 36:330–346. doi:10.1128/MCB.00832-15

    PubMed  Google Scholar 

  29. Yin H, Jiang Y, Li H et al (2011) Proteasomal degradation of myocardin is required for its transcriptional activity in vascular smooth muscle cells. J Cell Physiol 226:1897–1906. doi:10.1002/jcp.22519

    Article  CAS  PubMed  Google Scholar 

  30. Singh P, Li D, Gui Y, Zheng X-L (2017) Atrogin-1 increases smooth muscle contractility through myocardin degradation. J Cell Physiol 232:806–817. doi:10.1002/jcp.25485

    Article  CAS  PubMed  Google Scholar 

  31. Perry RLS, Yang C, Soora N et al (2009) Direct interaction between myocyte enhancer factor 2 (MEF2) and protein phosphatase 1alpha represses MEF2-dependent gene expression. Mol Cell Biol 29:3355–3366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pagiatakis C, Gordon JW, Ehyai S, Mcdermott JC (2012) A novel RhoA/ROCK-CPI-17-MEF2C signaling pathway regulates vascular smooth muscle cell gene expression. J Biol Chem 287:8361–8370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kelley LA, Mezulis S, Yates CM et al (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845–858. doi:10.1038/nprot.2015.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Imamura M, Long X, Nanda V, Miano JM (2010) Expression and functional activity of four myocardin isoforms. Gene 464:1–10. doi:10.1016/j.gene.2010.03.012

    Article  CAS  PubMed  Google Scholar 

  35. Creemers EE, Sutherland LB, McAnally J et al (2006) Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development. Development 133:4245–4256

    Article  CAS  PubMed  Google Scholar 

  36. Belaguli NS, Sepulveda JL, Nigam V et al (2000) Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators. Mol Cell Biol 20:7550–7558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morin S, Charron F, Robitaille L, Nemer M (2000) GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J 19:2046–2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mughal W, Nguyen L, Pustylnik S et al (2015) A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells. Cell Death Dis 6:e1944. doi:10.1038/cddis.2015.306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang J, Li A, Wang Z et al (2007) Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts. Mol Cell Biol 27:622–632

    Article  CAS  PubMed  Google Scholar 

  40. Gill G (2005) Something about SUMO inhibits transcription. Curr Opin Genet Dev 15:536–541. doi:10.1016/j.gde.2005.07.004

    Article  CAS  PubMed  Google Scholar 

  41. Callis TE, Cao D, Wang D-Z (2005) Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes. Circ Res 97:992–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Szklarczyk D, Franceschini A, Wyder S et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452. doi:10.1093/nar/gku1003

    Article  CAS  PubMed  Google Scholar 

  43. Huang J, Lu MM, Cheng L et al (2009) Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc Natl Acad Sci USA 106:18734–18739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ng WA, Grupp IL, Subramaniam A, Robbins J (1991) Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. Circ Res 68:1742–1750

    Article  CAS  PubMed  Google Scholar 

  45. Huang J, Elicker J, Bowens N et al (2012) Myocardin regulates BMP10 expression and is required for heart development. J Clin Invest 122:3678–3691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hom JR, Quintanilla RA, Hoffman DL et al (2011) The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell 21:469–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. doi:10.1016/j.cell.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  48. Tapscott SJ, Davis RL, Thayer MJ, Cheng PF (1988) MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Sci N Y, NY

    Google Scholar 

  49. Ieda M, Fu J-D, Delgado-Olguin P et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Qian L, Huang Y, Spencer CI et al (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485:593–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mohamed TMA, Stone NR, Berry EC et al (2017) Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135:978–995. doi:10.1161/CIRCULATIONAHA.116.024692

    Article  CAS  PubMed  Google Scholar 

  52. Fu J-D, Stone NR, Liu L et al (2013) Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep 1:235–247. doi:10.1016/j.stemcr.2013.07.005

    Article  CAS  Google Scholar 

  53. Nam Y-J, Song K, Luo X et al (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci USA 110:5588–5593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Belian E, Noseda M, Abreu Paiva MS et al (2015) Forward programming of cardiac stem cells by homogeneous transduction with MYOCD plus TBX5. PLoS ONE 10:e0125384. doi:10.1371/journal.pone.0125384

    Article  PubMed  PubMed Central  Google Scholar 

  55. Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79

    Article  CAS  PubMed  Google Scholar 

  56. Czubryt MP, Olson EN (2004) Balancing contractility and energy production: the role of myocyte enhancer factor 2 (MEF2) in cardiac hypertrophy. Recent Prog Horm Res 59:105–124

    Article  CAS  PubMed  Google Scholar 

  57. Sadoshima J, Izumo S (1997) The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol 59:551–571. doi:10.1146/annurev.physiol.59.1.551

    Article  CAS  PubMed  Google Scholar 

  58. Backs J, Olson EN (2006) Control of cardiac growth by histone acetylation/deacetylation. Circ Res 98:15–24

    Article  CAS  PubMed  Google Scholar 

  59. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42. doi:10.1038/nrg2485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cao D, Wang Z, Zhang C-L et al (2005) Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol Cell Biol 25:364–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang CL, McKinsey TA, Chang S et al (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110:479–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chang S, McKinsey TA, Zhang CL et al (2004) Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24:8467–8476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Czubryt MP, McAnally J, Fishman GI, Olson EN (2003) Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci USA 100:1711–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sparrow DB, Miska EA, Langley E et al (1999) MEF-2 function is modified by a novel co-repressor, MITR. EMBO J 18:5085–5098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lu J, Mckinsey TA, Nicol RL, Olson EN (2000) Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci USA 97:4070–4075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mckinsey TA, Zhang CL, Olson EN (2001) Control of muscle development by dueling HATs and HDACs. Curr Opin Genet Dev 11:497–504

    Article  CAS  PubMed  Google Scholar 

  67. McKinsey TA, Zhang CL, Lu J, Olson EN (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408:106–111. doi:10.1038/35040593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Grozinger CM, Schreiber SL (2000) Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc Natl Acad Sci USA 97:7835–7840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mckinsey TA, Zhang CL, Olson EN (2000) Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci USA 97:14400–14405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu Y, Randall WR, Schneider MF (2005) Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle. J Cell Biol 168:887–897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vega RB, Harrison BC, Meadows E et al (2004) Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol Cell Biol 24:8374–8385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. McKinsey TA (2007) Derepression of pathological cardiac genes by members of the CaM kinase superfamily. Cardiovasc Res 73:667–677

    Article  CAS  PubMed  Google Scholar 

  73. Harrison BC, Kim M-S, van Rooij E et al (2006) Regulation of cardiac stress signaling by protein kinase d1. Mol Cell Biol 26:3875–3888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fielitz J, Kim M-S, Shelton JM et al (2008) Requirement of protein kinase D1 for pathological cardiac remodeling. Proc Natl Acad Sci USA 105:3059–3063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Xing W, Zhang T-C, Cao D et al (2006) Myocardin induces cardiomyocyte hypertrophy. Circ Res 98:1089–1097

    Article  CAS  PubMed  Google Scholar 

  76. Badorff C, Seeger FH, Zeiher AM, Dimmeler S (2005) Glycogen synthase kinase 3beta inhibits myocardin-dependent transcription and hypertrophy induction through site-specific phosphorylation. Circ Res 97:645–654

    Article  CAS  PubMed  Google Scholar 

  77. Lockman K, Taylor JM, Mack CP (2007) The histone demethylase, Jmjd1a, interacts with the myocardin factors to regulate SMC differentiation marker gene expression. Circ Res 101:e115–e123

    Article  CAS  PubMed  Google Scholar 

  78. Zhang Q-J, Chen H-Z, Wang L et al (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121:2447–2456. doi:10.1172/JCI46277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yoshida T, Yamashita M, Horimai C, Hayashi M (2014) Kruppel-like factor 4 protein regulates isoproterenol-induced cardiac hypertrophy by modulating myocardin expression and activity. J Biol Chem 289:26107–26118. doi:10.1074/jbc.M114.582809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang EY, Biala AK, Gordon JW, Kirshenbaum LA (2012) Autophagy in the heart: too much of a good thing? J Cardiovasc Pharmacol 60:110–117. doi:10.1097/FJC.0b013e31824cc427

    Article  CAS  PubMed  Google Scholar 

  81. Huang J, Wang T, Wright AC et al (2015) Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development. Proc Natl Acad Sci USA 112:4447–4452. doi:10.1073/pnas.1420363112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Verzi MP, Agarwal P, Brown C et al (2007) The transcription factor MEF2C is required for craniofacial development. Dev Cell 12:645–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang J, Cheng L, Li J et al (2008) Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice. J Clin Invest 118:515–525

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Arnold MA, Kim Y, Czubryt MP et al (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12:377–389

    Article  CAS  PubMed  Google Scholar 

  85. Singh R, Park D, Xu J et al (2010) Struct2Net: a web service to predict protein–protein interactions using a structure-based approach. Nucleic Acids Res 38:W508–W515. doi:10.1093/nar/gkq481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gordon JW, Shaw JA, Kirshenbaum LA (2011) Multiple facets of NF-κB in the heart: to be or not to NF-κB. Circ Res 108:1122–1132

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

JWG is supported by the Natural Science and Engineering Research Council (NSERC) Canada and the Children’s Hospital Foundation of Manitoba. JWG is a member of the DEVOTION Research Cluster.

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Gordon, J.W. Regulation of cardiac myocyte cell death and differentiation by myocardin. Mol Cell Biochem 437, 119–131 (2018). https://doi.org/10.1007/s11010-017-3100-3

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